tbuckley/cabot-search huggingface dataset:
Myopenia and mechanisms of toxicity in older adults with colorectal cancer (CRC): The M&amp;M study (WF-1806).
Authors: Grant Richard Williams, Smita Bhatia, Heidi D. Klepin, Hanna Kelly Sanoff, Hyman B. Muss, Mustafa Al-Obaidi, Christian Harmon, Joshua Richman, Emily Van Meter Dressler, Mark Allen O'Rourke, Kathryn E. Weaver, Glenn Jay Lesser
Journal: Journal of Clinical Oncology (2022)

TPS3640 Background: CRC is the 2 nd most common cause of cancer death in the US, and nearly 60% of CRC cases occur among older adults. There is a critical unmet need to understand the underlying cause(s) of observed variability in chemotherapy toxicity (chemotoxicity) outcomes to minimize adverse outcomes and appropriately personalize therapy for older adults. Low muscle mass, known as myopenia, is prevalent in older adults with CRC (̃60%) and is associated with chemotoxicity and decreased overall survival (OS). However, little is known about trajectories of myopenia and underlying mechanisms of increased toxicities and decreased survival in myopenic patients. We address these gaps in a prospective cohort study, with the central goal of examining the role of myopenia in chemotoxicity in older adults with metastatic CRC undergoing 5-Fluouracil (5FU) based chemotherapy, and to explore the mediating influence of germline genetic variants and pharmacokinetics (PKs) in the association between myopenia and chemotherapy toxicity. Methods: This prospective cohort study is accruing through the Wake Forest NCI Community Oncology Research Program Research Base (WF NCORP) and funded by the NCI grants 2UG1CA189824 and K08CA234225. The study examines the impact of myopenia on chemotoxicity and OS in older adults with newly diagnosed metastatic CRC planning to receive systemic 5FU-based chemotherapy (either as monotherapy or in combination with oxaliplatin and/or irinotecan +/- biologics) (NCT03998202). All patients undergo the Cancer &amp; Aging Resilience Evaluation and Life-Space Evaluation at baseline, 3 and 6 months. Standard of care Computed Tomography (CT) images will be obtained to assess muscle measures (skeletal muscle area/density) at the L3 cross-section. The primary outcome is grades 3 to 5 chemotoxicity measured up to 6 months after initiation of chemotherapy using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. We will assess the association of baseline myopenia and trajectories of myopenia with severe chemotherapy toxicities. Secondary outcome measures include OS at 1 year and chemotoxicities using the Patient Reported Outcomes (PRO) version of the CTCAE. The study also explores the mediating/moderating influence of genetic variation and altered PKs (n = 60) in the association between myopenia and chemotherapy toxicity. To date, the study has accrued 73 of the 300 targeted patients from 110 NCORP practices. Clinical trial information: NCT03998202.
Evidence that life expectancy is increased in prostate cancer patients treated with low dose-rate (LDR) brachytherapy
Authors: S. Langley, J. Uribe, S. Uribe-Lewis, C. Deering, S. Langley, D. Higgins, S. Khaksar, S. Mehta, C. Mikropoulos, S. Otter, C. Perna
Journal: European Urology (2022)
Significance of induction chemotherapy combined with cetuximab in laryngeal preservation rate of locally advanced hypopharyngeal cancer.
Authors: Xia Xu, Xiong Liu, Wendong Tian, Huanhong Chen, Gang Li, Xiangping Li, Juan Lu, Xiaohong Peng, Bolong Yu
Journal: Journal of Clinical Oncology (2022)

e18078 Background: Anatomical and functional laryngeal organ preservation is critical for patients with locally advanced hypopharyngeal squamous cell carcinoma (LAHSCC). Induction chemotherapy with taxanes (T), cisplatin (P) and 5-FU (F) is a therapeutical option in patients with a strong desire to preserve the throat, whether enhanced induction chemotherapy (TPF/TP combined with cetuximab) can improve laryngeal preservation rate (LPR) and objective response rate (ORR) of LAHSCC remains controversial. Here we report the results of a retrospectively study comparing TPF/TP with TPF/TP plus cetuximab. Methods: Nanfang Hospital database was retrospectively queried for LAHSCC patients who received 2 cycle induction chemotherapy with TPF/TP (paclitaxel, cisplatin, 5-Fu) with or without concurrent use of cetuximab for ORR. Results: A total of 81 patients were identified including 36 which had concurrent use of TPF/TP and cetuximab. The overall ORR was 71.60% (58/81), patients in the TPF/TP +Cetuximab group had significantly improved ORR (83.33% (30/36) vs 62.22% (28/45) (P = 0.037) compared to TPF/TP group. After IC, 24 patients underwent laryngopharyngectomies, 6 underwent larynx-preserving surgeries, 51 underwent CCRT and 3 received salvage surgeries. In addition, the total 3-month laryngeal preservation rate (LPR) was 69.13% (56/81), the cetuximab-associated LPR benefit was observed in patients with 60.0% (27/45) in the TPF/TP group, and 80.56% (29/36) in the TPF/TP +Cetuximab group (P &lt; 0.001). The adverse events of grade 3 or 4 were similar between the two groups except for skin rash (TPF/TP group 6.7% vs TPF/TP+Cetuximab 41.7%, P &lt; 0.001), which gradually subsided within 2 weeks after the drug withdrawal. Conclusions: Concurrent cetuximab use with TPF/TP induction chemotherapy in LAHSCC patients was associated with improved ORR and short-term LPR, with tolerable toxicity. Further prospective evidence from larger trials is warranted.
Characterization of patients with metastatic melanoma that relapses following complete metabolic response from anti–PD-1 therapy.
Authors: Vincent T Ma, Yash Neeraj Agrawal, Leslie Anne Fecher, Christopher D. Lao
Journal: Journal of Clinical Oncology (2022)

9530 Background: Treatment with PD-1 inhibitor-based therapy has significantly improved survival in patients with metastatic melanoma over the past decade. Many of these patients achieve complete metabolic response (CMR) by FDG-PET/CT and electively stop treatment. However, the outcomes of patients who relapse after CMR remain uncertain. In this study, we attempt to further characterize metastatic melanoma patients who relapsed following elective discontinuation of anti-PD-1 based therapy due to CMR. Methods: We performed a single-center, retrospective analysis on a cohort of patients with metastatic or unresectable melanoma from 2012 to 2021 who were treated with anti-PD-1 monotherapy (pembrolizumab or nivolumab) or combination ipilimumab/nivolumab (I/N), with or without local therapies (surgery or radiation therapy). Patients who achieved a CMR from treatment were identified. CMR was defined as no evidence of metabolically active disease on full-body 18 F-FDG-PET/CT and no evidence of new intracranial metastasis on MRI brain. Multiple clinical variables and survival outcomes were assessed. Results: Among 386 advanced stage melanoma patients analyzed, 87 achieved a CMR followed by elective treatment cessation with a median anti-PD-1 therapy duration of 10.4 months. 19/87 patients had brain metastasis at baseline. 17/87 patients had disease relapse with a median time to relapse from CMR of 12.1 months. Of those 17 patients, 8 received I/N, 9 received anti-PD-1 monotherapy, and 2 required local therapies to obtain CMR. 7/17 patients were able to achieve CMR again following resumption of anti-PD-1 monotherapy (n = 6) and BRAF/MEK targeted therapy (n = 1). 10/17 patients relapsed in the brain with 7 of those patients having no history of brain metastasis at baseline. Median overall survival after relapse from CMR was 34.1 months. The most common cause of death following relapse from CMR was brain metastasis progression (n = 5). Conclusions: A small proportion of metastatic melanoma patients who achieve complete metabolic (CMR) following treatment with anti-PD-1 therapy develop disease relapse. We found that relapse in the brain is common, regardless of baseline involvement at time of therapy, and is a common cause of mortality suggesting the importance of intracranial surveillance following treatment cessation. Ongoing studies are warranted to identify clinicopathologic factors that predict relapse to better inform patients and providers who elect to stop anti-PD-1 therapy.
Racial differences in the mutational landscape of serous endometrial cancer.
Authors: Julian C. Schink, Ruchi Garg, Barbara Buttin, Julia Andrea Elvin, Natalie Godbee, Amber Moran, Vicki Doctor, Bradford A. Tan, John H. Farley, Maurie Markman
Journal: Journal of Clinical Oncology (2022)

5600 Background: Tumor comprehensive genomic profiling (CGP) identifying genomic alterations (GA) that have diagnostic, prognostic and are potentially therapeutically targetable is essential to precision oncology. 2022 NCCN Uterine Neoplasm guidelines recommend tumor genetic evaluation as part of initial evaluation. As racial disparities in endometrial cancer outcomes have been widely reported, we analyzed our CGP results from a large series of serous endometrial cancer patients treated in a nationwide cancer network to identify GA differences that may contribute to worse prognosis and help inform better therapy selection. Methods: 86 Pts with serous endometrial underwent hybrid-capture based CGP for up to 324 cancer-related genes of archival tumor tissue or 62 genes on circulating tumor DNA ordered during clinical care for treatment decision-making between 01-2013 to 07-2021. Clinically relevant genomic alterations (CRGA) were defined as associated with targeted therapies or mechanism-driven clinical trials. Statistical analysis performed with Fisher Exact test comparing Black and White women. Results: Median age was 63 years (range, 38-85), 37% were White, 58% were Black and 5% were Asian. GA were identified in 94% (81/86) of these patients. TP 53 mutations which is characteristic of serous cancer were present in 80 of 86 patients (93%). GA predicted to activate PI3-Kinase pathway signaling ( PIK3CA, PIK3R1, PTEN) were significantly more common in White women occurring in 13 of 32 (41%), compared with 8 of 50 (16%) of Black women (p. &lt; 0.02). An important, but not statistically significant trend of greater percentage of CCNE1 amplification in Black women is also noted, see table below: Mutation frequencies were similar between Black and White women for the following genes: PPP2R1A 23%; MYC 19%; FBXW7 14%; ARID1A 9%. Conclusions: In this 86 patient series of women with Serous Endometrial Cancer we note that PIK3CA mutations, an important resistance factor in anti-HER2 therapy, were significantly more common in White women (41%) compared with Black women (16%) (p. &lt; 0.02) and ERBB2 mutations occurred in 19% of White women and only 10% of Black women. This study cohort also identified a larger percentage of black women with CCNE1 amplification. Increased CCNE1 amplification has been linked to the racial disparities in cancer outcomes and may explain the disparities seen with endometrial cancers. [Table: see text]
EPIK-B5: A phase III, randomized study of alpelisib (ALP) plus fulvestrant (FUL) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), <i>PIK3CA</i>-mutated advanced breast cancer (ABC) progressing on/after an aromatase inhibitor (AI) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i).
Authors: Michelino De Laurentiis, Luis Costa, Joseph Gligorov, Ann Knop, Elzbieta Senkus-Konefka, José A. García-Sáenz, Peter Schmid, Aurelia Heniquez, Paolo Serra, Albert Reising, Sherko Kuemmel
Journal: Journal of Clinical Oncology (2022)

TPS1109 Background: Endocrine therapy (ET) + CDK4/6i is standard of care for HR+, HER2− ABC; however, CDK4/6i resistance, in which the phosphatidylinositol-3-kinase (PI3K) pathway has a key role, remains challenging. Progression-free survival (PFS) for ≥ 2nd-line ET monotherapy post CDK4/6i is poor; prognosis may be worse in patients with a PI3KCA mutation. ALP (PI3K-α selective inhibitor and degrader) + FUL is approved by the European Medicines Agency (EMA) for HR+, HER2–, PIK3CA-mutated ABC after ET monotherapy. Outside the EMA, ALP + FUL approval includes post-CDK4/6i use. ALP + FUL has shown clinical activity and consistent safety in a small subpopulation in SOLAR-1 with prior CDK4/6i treatment (n = 9) and in BYLieve Cohort A (CDK4/6i + AI as immediate prior treatment; n = 121). The EPIK-B5 study aims to confirm the efficacy and safety of ALP + FUL in a larger population with HR+, HER2–, PIK3CA-mutated ABC with prior CDK4/6i + AI treatment. Methods: EPIK-B5 is a Phase III, randomized (1:1), double-blind, placebo-controlled study assessing the efficacy and safety of ALP (300 mg/d orally starting Cycle 1 Day 1 [C1D1]) + FUL (500 mg intramuscularly on C1D1 and C1D15, and D1 of subsequent cycles) in patients (N ≈ 234) with HR+, HER2–, PIK3CA-mutated ABC progressing on/after CDK4/6i + AI. Patients randomized to placebo + FUL can cross over to ALP + FUL after progression. Randomization is stratified by presence of lung and/or liver metastasis and prior CDK4/6i setting. Adult men or postmenopausal women with confirmed HR+, HER2–, PIK3CA-mutated ABC and ≥ 1 measurable lesion are eligible. The primary endpoint is PFS per blinded independent review committee assessment. Secondary endpoints include overall survival, overall response and clinical benefit rates, duration of and time to response, PFS by PIK3CA-mutation status in circulating tumor DNA, PFS on next-line treatment, time to definitive deterioration of ECOG status, quality of life (QoL), and safety and tolerability. Exploratory endpoints include biomarker analyses, additional QoL endpoints, and time to subsequent chemotherapy. Recruitment is ongoing, with enrollment planned over 2 years in 18 countries; completion of primary data collection is anticipated in 2026. Clinical trial information: NCT05038735; EUDRACT2021-001966-39.
Phase Ib INEOV neoadjuvant trial of durvalumab +/- tremelimumab with platinum chemotherapy for patients (pts) with unresectable ovarian cancer (OC): Final complete resection and pathological response rates.
Authors: Alexandra Leary, Thibault De La Motte Rouge, Alain Lortholary, Bernard Asselain, Jerome Alexandre, Anne Floquet, Aude Marie Savoye, Nicolas Delanoy, Céline Gavoille, Benoit You, Veronique D'hondt, Julien Grenier, Catherine Genestie, Laure Chardin, Eric Pujade-Lauraine
Journal: Journal of Clinical Oncology (2022)

5557 Background: We have shown that neoadjuvant carboplatin and paclitaxel (NACP) increased tumor infiltrating lymphocytes and PDL1 expression in OC pts. INEOV evaluated NACP with durvalumab (D) +/- tremelimumab (T) in pts with unresectable OC. We previously reported that NACP with D+/-T was feasible and safe but the addition of T did not improve interval debulking surgery (IDS) rates after 3 cycles (C3) (ESMO 2021). Here we provide an update with longer follow up including data on delayed IDS performed after 6 cycles of neoadjuvant treatment. Key secondary endpoints include complete resection (CC0) and complete pathological response rates. Methods: Pts with stage IIIC/IV OC were randomized to NACP + D (1125mg) alone (arm A) or with T (75mg once at C2) (arm B). Interval debulking surgery (IDS) was planned after C3, or delayed after C6. Pts in arm A not operable after C3 crossed over to arm B, pts in arm B crossed over to standard of care (SOC). Pts were assessed for delayed IDS after C6. Complete pathological response (pCR) was defined as no residual tumor cells found on any surgical specimens, or no residual tumor cells on any samples outside the ovary at IDS. Results: Sixty four (N = 64) of 66 pts (IIIC/IV: 70%/30%) randomized were evaluable. After C3, 66% (21/32) of pts in arm A and 59% (19/32) in arm B had IDS. The 11 pts in arm A not candidate for IDS after C3 crossed over to arm B until C6 and 5/11 benefited from delayed IDS. The 13 pts in arm B inoperable at C3 went on to receive SOC (NACP +/- bevacizumab), and 5/13 became eligible for delayed IDS after C6. Overall, IDS was performed in 50 of 64 evaluable pts, and most (45/50) achieved macroscopically complete resection (CC0), so that the overall CC0 rate was 70% (45/64), with no significant difference between arms (CC0 = 75% vs 65% in arm A vs B). Among the 50 pts who had IDS, complete pathological responses were observed in 18% of pts. Conclusions: Taking into account the whole treatment strategy including delayed IDS after 6 cycles of neoadjuvant treatment, we have shown that neoadjuvant CP with D+/- T results in encouraging CC0 (70%) and pCR (18%) rates. However there was no apparent benefit to the addition of T to D. Studies are ongoing to describe the immune features predictive of pCR as well as the impact of treatment on the immune microenvironment. Clinical trial information: NCT03249142.
Combined IL-6 and IL-8 inhibition to overcome mesenchymal stem cell (MSC)-induced resistance to antimetastatic drugs in osteosarcoma.
Authors: S. Rubina Baglio, Celine De Schrijver, Crescenzo Massaro, Tonny Lagerweij, Cristina Gomez Martin, Cristina Giorgio, Laura Brandolini, Elizabeth Marie Gavioli, Marcello Allegretti, D. Michiel Pegtel
Journal: Journal of Clinical Oncology (2022)

10037 Background: Mesenchymal stem cells (MSCs) play a key role in the progression of osteosarcoma (OS). In response to tumor-associated signals, including tumor-secreted extracellular vesicles (EVs), MSCs increase the expression of inflammatory cytokines promoting tumor cell aggressiveness. Previous data has demonstrated that IL-6 and IL-8 signaling mediate metastasis in OS. The aim of this study was to evaluate tumor EV-induced alterations of MSCs and identify combination therapies that can counteract MSC-induced resistance to antimetastatic drugs. Methods: Tumor EV-induced alterations of the MSC transcriptome were analyzed by RNA-seq. Gene set enrichment analysis (GSEA) was applied to discriminate TGFβ-dependent and independent pathways. EV RNA-induced expression changes were identified by transfecting purified EV-RNA in MSCs and by using a selective dsRNA antagonist. We selected candidate targets to block MSC-induced drug resistance and evaluated their effect in an orthotopic xenograft model of OS. Ladarixin (an allosteric inhibitor of the CXCL8/IL-8 receptors CXCR1 and CXCR2; 30 mg/kg 6x per week i.p.) and tocilizumab (anti-IL6 receptor antibody; 100 µg/mouse every other day i.p.) were administered starting from day one until the experimental endpoint. Metastasis were quantified by histological examination. This study was funded by the Dutch Cancer Society (KWF), POR FESR Campania 2014‐2020 and Dompé Farmaceutici SpA. Results: EVs from aggressive cancer cell lines induced an inflammatory MSC (iMSC) phenotype, characterized by increased expression of chemokines, including IL-8 as the most upregulated. Apart from IL-6, these alterations were mostly independent from TGFβ signaling and related to pattern recognition receptor (PRR) activation. We demonstrated that tumor EV-associated non-coding RNAs trigger TLR3 signaling in MSCs activating an innate immune response leading to high induction of IL-8 and other chemokines. Ladarixin and tocilizumab combination significantly reduced metastasis formation in a spontaneous metastasis model and overcame iMSC-induced resistance observed with single antimetastatic treatments. No effect was observed on primary tumor growth. Conclusions: EV-associated TGFβ together with EV-RNA induce iMSCs development in OS. Ladarixin in combination with tocilizumab reduced metastasis formation in a xenograft mouse model of OS, and, importantly, may prevent the occurrence of iMSC-induced tumor resistance to antimetastatic drugs.
From Skepticism to Hope: The Evolving Concept of the Initiation and Use of Sodium-Glucose Cotransporter 2 Inhibitors in Hospitalized Patients
Authors: Theocharis Koufakis, Omar G. Mustafa, Ramzi A. Ajjan, Xavier Garcia-Moll, Pantelis Zebekakis, George Dimitriadis, Kalliopi Kotsa
Journal: Drugs (2022)
Automated imaging-based prognostication (IPRO) for stage I non-small cell lung cancer using deep learning applied to computed tomography.
Authors: Felipe Soares Torres, Shazia Akbar, Srinivas Raman, Kazuhiro Yasufuku, Thomas Jay Hannessy, Felix Baldauf-Lenschen, Natasha B. Leighl
Journal: Journal of Clinical Oncology (2022)

e20575 Background: Computed tomography (CT) imaging is used to inform staging and treatment decisions for stage I non-small cell lung cancer (NSCLC) patients. We have previously used deep learning applied to pretreatment CTs to generate an imaging-based prognostication (IPRO) score that automatically quantifies mortality risk and stratifies patients beyond tumor, node, metastasis (TNM) substages. Here we present validation data of its prognostic impact. Methods: We developed a fully automated deep learning model, IPRO, designed to process a CT scan, localize the 36cm 3 space centered on the lungs, and learn prognostic imaging features to predict mortality risk. IPRO was trained on pretreatment CTs acquired from 1,696 patients treated for NSCLC at a tertiary care center between 2004 and 2018. We withheld 20% of the cases for validation, including 162 patients that were diagnosed with stage I NSCLC by clinical staging. We evaluated IPRO’s ability to stratify stage I NSCLC patients into mortality risk quintiles using the Cox proportional hazards model and assessed differences in median overall survival (mOS). Results: Of the 162 stage I NSCLC patients in the validation set, the mOS was 68.5 months (95% CI 66.7-69.6), 85 (52.5%) were male, and 125 (77.2%) were diagnosed with stage IA. Of these, 111 patients received surgery, 40 received radiotherapy (RT), 9 received surgery + adjuvant systemic therapy (ST), and 2 patients received surgery + ST + RT. According to IPRO, the patients predicted to have the highest risk had significantly increased 5-year mortality compared to those predicted to have the lowest risk (OR 8.4, 95% CI 2.4-29.2, p &lt; 0.01); median survival 48.0 months and 69.5 months, respectively. Conclusions: Deep learning applied to pretreatment CTs provides personalized prognostic insights for stage I NSCLC beyond current TNM staging. [Table: see text]
A community approach to the cancer-variant-interpretation bottleneck
Authors: Kilannin Krysiak, Arpad M. Danos, Susanna Kiwala, Joshua F. McMichael, Adam C. Coffman, Erica K. Barnell, Lana Sheta, Jason Saliba, Cameron J. Grisdale, Lynzey Kujan, Shahil Pema, Jake Lever, Nicholas C. Spies, Andreea Chiorean, Damian T. Rieke, Kaitlin A. Clark, Payal Jani, Hideaki Takahashi, Peter Horak, Deborah I. Ritter, Xin Zhou, Benjamin J. Ainscough, Sean Delong, Mario Lamping, Alex R. Marr, Brian V. Li, Wan-Hsin Lin, Panieh Terraf, Yasser Salama, Katie M. Campbell, Kirsten M. Farncombe, Jianling Ji, Xiaonan Zhao, Xinjie Xu, Rashmi Kanagal-Shamanna, Kelsy C. Cotto, Zachary L. Skidmore, Jason R. Walker, Jinghui Zhang, Aleksandar Milosavljevic, Ronak Y. Patel, Rachel H. Giles, Raymond H. Kim, Lynn M. Schriml, Elaine R. Mardis, Steven J. M. Jones, Gordana Raca, Shruti Rao, Subha Madhavan, Alex H. Wagner, Obi L. Griffith, Malachi Griffith
Journal: Nature Cancer (2022)